Coexistence of the 677C>T and 1298A>C MTHFR polymorphisms and its significance in the population of Polish women

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1 DOI: 10./gp/59559 Ginekol Pol. 015, 86, Coexistence of the 6C>T and 198A>C MTHFR polymorphisms and its significance in the population of Polish women Znaczenie współwystępowania polimorfizmów 6C>T oraz 198A>C genu MTHFR u kobiet w populacji polskiej 1 Division of Perinatology and Women s Diseases, Poznan University of Medical Sciences, Poland Division of Gynecology and Obstetrics, Podhale Multidisciplinary Hospital, Nowy Targ, Poland Laboratory of Molecular Biology in the Division of Perinatology and Women s Diseases, Poznan University of Medical Sciences, Poznan, Poland Student Scientific Association of Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poland Abstract Objectives: The aim of the study was to evaluate the frequency of the 6C>T and 198A>C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene, as well as the coexistence of both these genetic variants in women from the Polish population. Material and methods: A total of 66 women from the Polish population were enrolled in the study group. The frequency of the investigated genotypes of the 6C>T and 198A>C polymorphisms of the MTHFR gene was analyzed with the use of PCR/RFLP methods. Results: The frequency of the 6CC, 6CT and 6TT genotypes in the studied population of women was 50.60%, 9.88% and 9.5%, respectively. As to the 198AA, 198AC and 198CC genotypes, the obtained results were as follows:.5%,.88% and 9.%, respectively (Tables II and III). Simultaneous analysis revealed the most frequent coexistence of 6CC/198AC (8.85%), 6CT/198AA (0.85%) and 6CT/198AC (19.0%) genotypes. The coexistence of 6CC/198AA (1.9%), 6CC/198CC (9.%) and 6TT/198AA (9.51%) genotypes was observed less frequently. In the studied population of Polish women, the coexistence of 6CT/198CC, 6TT/198AC and 6TT/198CC genotypes has been not observed. Conclusions: The frequency and coexistence of genotypes of the 6C>T and 198A>C MTHFR gene polymorphisms in the studied population of Polish women is similar to other NorthEuropean populations. Women carriers of the mutated variants of both, 6C>T and 198A>C polymorphisms of the MTHFR gene should receive special perinatal care in order to prevent fetal defects and thrombosisrelated complications during pregnancy. It is vital to emphasize the significance of proper education of folate supplementation, especially in pregnant patients and women of reproductive age. Key words: MTHFR / / / Corresponding author: Hubert Wolski Division of Perinatology and Women s Disease Poznan University of Medical Sciences Tel , fax hubertwolski@wp.pl Otrzymano: Zaakceptowano do druku: Polskie Towarzystwo Ginekologiczne Nr 10/015

2 Ginekol Pol. 015, 86, DOI: 10./gp/59559 Hubert Wolski et al. Coexistence of the 6C>T and 198A>C MTHFR polymorphisms and its significance in the population of Polish women. Streszczenie Cel: Określenie częstości występowania polimorfizmów 6C>T i 198A>C genu kodującego reduktazę metylenotetrahydrofolianową (MTHFR) oraz ocena współwystępowania obydwu wariantów genetycznych u kobiet w populacji polskiej. Materiał i metoda: Do grupy badawczej włączono 66 kobiety z populacji polskiej. Częstość występowania genotypów polimorfizmów 6C>T oraz 198A>C genu MTHFR została zbadana metodą PCR/RFLP. Wyniki: W badanej grupie częstość występowania genotypów 6CC, 6CT oraz 6TT wynosiła odpowiednio 50,60%, 9,88% oraz 9,5%. Natomiast genotypy 198AA, 198AC oraz 198CC występowały z częstością,5%,,88% oraz 9,%. Jednocześnie analiza współwystępowania genotypów pozwoliła na określenie najczęściej występujących genotypów 6CC/198AC (8,85%), 6CT/198AA (0,85%), 6CT/198AC (19,0%). Współwystępowanie genotypów 6CC/198AA (1,9%), 6CC/198CC (9,%), 6TT/198AA (9,51%) było obserwowane rzadziej. W badanej populacji nie zaobserwowano współwystępowania polimorfizmów 6CT/198CC, 6TT/198AC, 6TT/198CC. Wnioski: Częstość występowania i współwystępowania polimorfizmów 6C>T i 198A>C u kobiet w populacji polskiej jest porównywalna do częstości występowania tych wariantów w innych populacjach północnoeuropejskich. Kobiety, nosicielki zmutowanych genotypów polimorfizmów 6C>T i 198A>C genu kodującego MTHFR, powinny zostać objęte specjalną opieką perinatalną, z powodu wzrostu ryzyka wystąpienia wad płodu oraz powikłań zakrzepowych w czasie ciąży. Należy zwrócić uwagę na właściwą edukację i suplementację folianami kobiet, szczególnie w wieku rozrodczym oraz w czasie ciąży. Słowa kluczowe: MTHFR / / / Introduction MTHFR 6C>T 198A>C 6C>T 6TT 198A>C 6C>T 198A>C 6TT 198CC 198C 6CT/198AC 6TT/198AA 6TT/198AA 6CT/198AC MTHFR 6C>T 198A>G MTHFR Objectives 6C>T 198A>C MTHFR Material and methods Study group Nr 10/015 Polskie Towarzystwo Ginekologiczne

3 DOI: 10./gp/59559 Ginekol Pol. 015, 86, Hubert Wolski et al. Coexistence of the 6C>T and 198A>C MTHFR polymorphisms and its significance in the population of Polish women. Table I. MTHFR activity [%] according to the presence of 6C>T and 198A>C polymorphisms [Put, Weisberg]. 198A>C MTHFR Genotypes 6C>T MTHFR CC (%) CT (%) TT (%) AA (%) AC (%) CC (%) 5060 Table II. The frequency of genotypes and alleles of 6C>T MTHFR gene polymorphism. Polymorphism Genotypes Observed value (%) Expected value (%) CC 5 (50.60) 9.6 CT 6 (9.88) 1.56 TT 6 (9.5) 8.68 MTHFR 6C>T Total 66 (100.00) Alleles C 9 (0.5) T 90 (9.6) Total 1 (100.00) Table III. The frequency of genotypes and alleles of 198A>C MTHFR gene polymorphism. Polymorphism Genotypes Observed value (%) Expected value (%) AA 8 (.5).8 AC (.88). CC 6 (9.) MTHFR 198 A>C Total 66 (100.00) Alleles A 88 (66.69) C 1 (.1) Total 1 (100.00) Table IV. The frequency of coexistence of 6C>T and 198A>C polymorphisms. 198A>C MTHFR 6C>T MTHFR CC CT TT Total AA 8 (1.9) 18 (0.85) 6 (9.51) 8 (.5) AC 191 (8.85) 16 (19.0) 0 (0.00) (.88) CC 6 (9.) 0 (0.00) 0 (0.00) 6 (9.) Total 5 (50.61) 6 (9.88) 6 (9.51) 66 (100.00) Genetic analysis 6C>T 198A>C 6C>T 198A>C Hinf Mbo 6CC 6CT 6TT AA AC CC Polskie Towarzystwo Ginekologiczne Nr 10/015

4 Ginekol Pol. 015, 86, DOI: 10./gp/59559 Hubert Wolski et al. Coexistence of the 6C>T and 198A>C MTHFR polymorphisms and its significance in the population of Polish women. Table V. Coexistence of 6C>T and 198A>C polymorphisms in different populations. Author Population Study group Isotalo i wsp., 000 van der Put i wsp., 1998 De Re i wsp., 010 Kumar Rai i wsp., 005 Rady i wsp, 1999 Sazci i wsp., 005 Bodurogulu i wsp., 005 Ergul i wsp., 00 Canadian newborns 119 Dutch women/men 0 Italian n women/men 5 men 15 women 19 Hindu women 159 Ashkenazi/ Caucasian women/men 186 women/men 18 Turkish women/men 168 Turkish children 9 fathers mothers 80 Turkish women 19 MTHFR 6C>T/MTHFR 198A>C N (%) CC/AA CC/AC CC/CC CT/AA CT/AC CT/CC TT/AA TT/AC TT/CC (1.0) 6 (15.0) (5.0) 19 (60) 5 (.60) (0.80) (.0) 1 (8.10) 8 (10.60) 11 (11.80) (.0) (5.00) 5 (18.10) (5.0) 105 (6.10) 90 (19.80) 58 (18.0) (.00) 59 (.10) 50 (6.90) (15.50) 01 (.80) 1 (1.00) 10 (1.90) (1.5) 5 (.0) 9 (.60) 8 (9.0) 8 (8.0) (.0) 15 (10.80) (1.80) 0 (10.80) 1 (8.10) 16 (8.0) (.50) 10 (1.90) (5.00) 1 (.0) 1 (11.0) 81 (0.10) 98 (1.60) 0 (.0) 8 (0.10) 1 (1.0) 19 (10.0) 9 (19.60) 11 (.0) 8 (0.10) 8 (8.90) (1.5) 8 (.90) (19.0) 81 (0.10) (0.0) 95 (0.0) (0.0) 1 (8.80) 9 (1.00) (.0) 6 (1.60) 6 (8.00) (.50) (8.5) 5 (18.10) (0.0) 1 (0.0) (1.0) (.50) (1.00) (.10) 1 (10.10) 6 (9.00) 5 (1.60) (1.00) 1 (9.0) (1.0) 5 (1.0) 9 (6.0) 16 (8.0) 8 (8.60) (.80) (8.5) (.60) (1.0) (1.5) 5 (1.60) (1.0) (1.90) 1 (0.60) (1.00) 5 (.60) Results 6CC 6CT 6TT 198AA, 198AC 198CC 6CC/198AC 6CT/198AA 6CT/198AC 6CC/198AA 6CC/198CC 6TT/198AA 6CT/198CC 6TT/198AC 6TT/198CC Discussion 6C>T 198A>C MTHFR 6TT/198AA 6CT/198AC 6TT/198AA 6CC/198CC 6CT/198AA 6CT/198CC 6TT/198AC 6TT/198CC 6CT/198AC 6TT/18AA MTHFR 6CT/198AC Nr 10/015 Polskie Towarzystwo Ginekologiczne 5

5 DOI: 10./gp/59559 Ginekol Pol. 015, 86, Hubert Wolski et al. Coexistence of the 6C>T and 198A>C MTHFR polymorphisms and its significance in the population of Polish women. 6CT/198AC 6CT/198AC 6CC/198AC 6TT/198CC 6CC/198AC 6CT/198AA 6TT/198AA 6TT/198CC 6CT/198CC 6TT/198AC 6CT/198CC 6TT/198AC 6CT/198CC 6TT/198AC 6C>T 198A>C MTHFR 6CT/198AC 6CT/198CC 6TT/198AC MTHFR 6T 6T 6T 6C>T 6C>T 6TMTHFR 6CC 6TMTHFR 6T MTHFR MTHFR 6C>T 198A>C 6TT, 198CC, 6CT/198AC 6TT/198AA Conclusions 6C>T 198A>C MTHFR 6C>T 198A>C MTHFR Oświadczenie autorów 1. Hubert Wolski autor koncepcji i założeń pracy, przygotowanie anuskryptu i piśmiennictwa, ostateczna korekta i akceptacja manuskryptu autor zgłaszający i odpowiedzialny za manuskrypt.. Maria Kocięska zebranie materiału, analiza statystyczna wyników, przygotowanie manuskryptu.. Aleksandra E. Mrozikiewicz współautor tekstu pracy, korekta i aktualizacja literatury. Magdalena Barlik analiza i interpretacji wyników, współautor tekstu pracy. 5. Grażyna Kurzawińska współautor tekstu pracy, analiza statystyczna wyników. Źródło finansowania: badania statutowe Kliniki Perinatologii i Chorób Kobiecych UM w Poznaniu nr: Konflikt interesów: Autorzy nie zgłaszają konfliktu interesów oraz nie otrzymali żadnego wynagrodzenia związanego z powstawaniem pracy 6 Polskie Towarzystwo Ginekologiczne Nr 10/015

6 Ginekol Pol. 015, 86, DOI: 10./gp/59559 Hubert Wolski et al. Coexistence of the 6C>T and 198A>C MTHFR polymorphisms and its significance in the population of Polish women. References 1. Chiang FF, Huang SC, Wang HM, [et al.]. High serum folate might have a potential dual effect on risk of colorectal cancer. Clin Nutr. 01 Nov 8. pii: S061561(1)006. doi: /j. clnu McGarel C, Pentieva K, Strain JJ, McNulty H. Emerging roles for folate and related Bvitamins in brain health across the lifecycle. Proc Nutr Soc. 01, 5, Catena C, Colussi G, Nait F, [et al.]. Elevated homocysteine levels are associated with the metabolic syndrome and cardiovascular events in hypertensive patients. Am J Hypertens. 01 Dec 1. pii: hpu8.. Mandaviya PR, Stolk L, Heil SG. Homocysteine and DNA methylation: A review of animal and human literature. Mol Genet Metab. 01, 11, 5. doi: /j.ymgme Scazzone C, Bono A, Tornese F, [et al.]. Correlation between low folate levels and hyperhomocysteinemia, but not with vitamin B1 in hypertensive patients. Ann Clin Lab Sci. 01,, SeremakMrozikiewicz A. Znaczenie metabolizmu folianów w rozwoju powikłań u kobiet ciężarnych. Ginekol Pol. 01, 8, 8.. SeremakMrozikiewicz A. Implikacje kliniczne metabolizmu folianów. Ginekol Pol. 01,, Iacobazzi V, Infantino V, Castegna A, Andria G. Hyperhomocysteinemia: related genetic diseases and congenital defects, abnormal DNA methylation and newborn screening issues. Mol Genet Metab. 01, 11,. doi: /j.ymgme Frosst P, Blom HJ, Milos R, [et al.]. A candidate genetic risk factor for vascular disease: a common mutation methylenetetrahydrofolate reductase. Nat Genet. 1995, 10, Rozen R. Molecular genetics of Methylenetetrahydrofolate reductase deficiency. J Inher Metab Dis. 1996, 19, van der Put NM, Gabreëls F, Stevens EM, [et al.]. A second common mutation in the methylenetetrahydrofolate reductase Gene: An Additional Risk Factor for NeuralTube Defects? Am J Hum Genet. 1998, 6, Hughes LB, Beasley TM, Patel H, [et al.]. Racial or ethnic differences in allele frequencies of singlenucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann Rheum Dis. 006, 65, Robien K, Ulrich CM. 5,10methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview. Am J Epidemiol 00, 15, Binia A, Contreras AV, CanizalesQuinteiros S, [et al.]. Geographical and ethnic distribution of single nucleotide polymorphism within genes of the folate/homocysteine pathway metabolism. Genes Nutr. 01, 9, 1. doi: /s Weisberg I, Tran P, Chritensen B, [et al.]. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998, 6, Hanson NQ, Aras O, Yang F, Tsai MY. C6T and A198C polymorphisms of the methylenetetrahydrofolate reductase gene: incidence and effect of combined genotypes on plasma fasting and postmethionine load homocysteine in vascular disease. Clin Chem. 001,, Zappacosta B, Graziano M, Persichilli S, [et al.]. 5,10Methylenetetrahydrofolate reductase (MTHFR) C6T and A198C polymorphisms: genotype frequency and association with homocysteine and folate levels in middlesouthern Italian adults. Cell Biochem Funct. 01,, Yang B, Liu Y, Li Y, [et al.]. Geographical distribution of MTHFR C6T, A198C and MTRR A66G gene polymorphisms in China: findings from 155 adults of Han nationality. PLoS One. 01;8():e59. doi: 10.1/journal.pone AntonioVéjar V, Del MoralHernández O, AlarcónRomero LC, [et al.]. Ethnic variation of the C6T and A198C polymorphisms in the methylenetetrahydrofolatereductase (MTHFR) gene in southwestern Mexico. Genet Mol Res. 01, 1, Ozen F, Sen M, Ozdemir O. Methylenetetrahydrofolate reductase gene germline C6T and A198C SNPs are associated with colorectal cancer risk in the Turkish population. Asian Pac J Cancer Prev. 01, 15, GuéantRodriguez RM, Guéant JL, Debard R, [et al.]. Prevalence of methylenetetrahydrofolate reductase 6T and 198C alleles and folate status: a comparative study in Mexican, West African, and European populations. Am J Clin Nutr. 006, 8, de Re V, Cannizzaro R, Canzonieri V, [et al.]. MTHFR polymorphisms in gastric cancer and in firstdegree relatives of patients with gastric cancer. Tumor Biol. 010, 1,.. Sazci A, Ergul E, Kaya G, Kara I. Genotype and allele frequencies of the polymorphic methylenetetrahydrofolate reductase gene in Turkey. Cell Biochem Funct. 005,, Ergul E, Sazci A, Utkan N, Canturk Z. Polymorphisms in the MTHFR gene are associated with breast cancer. Tumour Biol. 00,, Boduroğlu K, Alanay Y, Alikaşifoğlu M, [et al.]. Analysis of MTHFR 198A>C in addition to MTHFR 6C>T polymorphism as a risk factor for neural tube defects in the Turkish population. Turk J Pediatr. 005,,. 6. Kumar Rai A, Singh S, Mehta S, [et al.]. MTHFR C6T and A198C polymorphisms are risk factors for Down s syndrome in Indian mothers. J Hum Genet. 006, 51, 88.. Rady P, Tyring S, Hudnall D, [et al.]. Methylenetetrahydrofolate reductase (MTHFR): the incidence of mutations C6T and A198C in the Ashkenazi Jewish population. Am J Med Genet. 1999, 86, Isotalo PA, Wells GA, Donnelly JG. Neonatal and Fetal Methylenetetrahydrofolate Reductase Genetic Polymorphisms: An Examination of C6T and A198C Mutations. Am J Hum Genet. 000, 6, Lucock M, Yates Z. Folic acid vitamin and panacea or genetic time bomb? Nat Rev Genet. 005, 6, Lucock M, Glanville T, Ovadia L, [et al.]. Photoperiod at conception predicts C6TMTHFR genotype: A novel geneenvironment interaction. Am J Hum Biol. 010,, 889. doi: /ajhb Yafei W, Lijun P, Jinfeng W, Xiaoying Z. Is the prevalence of MTHFR C6Tpolimorphism associated with ultraviolet radiation in Eurasia? J Hum Genet. 01, 5, Nr 10/015 Polskie Towarzystwo Ginekologiczne